Cellular basis of abnormal calcium transients of failing human ventricular myocytes

Depressed contractility is a central feature of the failing human heart and has been attributed to altered [Ca²⁺]_i. This study examined the respective roles of the L-type Ca₂₊ current (I_Ca), SR Ca²⁺ uptake, storage and release, Ca²⁺ transport via the Na⁺-Ca²⁺ exchanger (NCX), and Ca²⁺ buffering in the altered Ca²⁺ transients of failing human ventricular myocytes. Electrophysiological techniques were used to measure and control V_m and measure I_m, respectively, and Fluo-3 was used to measure [Ca²⁺]_i in myocytes from nonfailing (NF) and failing (F) human hearts. Ca²⁺ transients from F myocytes were significantly smaller and decayed more slowly than those from NF hearts. Ca²⁺ uptake rates by the SR and the amount of Ca²⁺ stored in the SR were significantly reduced in F myocytes. There were no significant changes in the rate of Ca²⁺ removal from F myocytes by the NCX, in the density of NCX current as a function of [Ca²⁺]_i, I_Ca density, or cellular Ca²⁺ buffering. However, Ca²⁺ influx during the late portions of the action potential seems able to elevate [Ca²⁺]i in F but not in NF myocytes. A reduction in the rate of net Ca²⁺ uptake by the SR slows the decay of the Ca²⁺ transient and reduces SR Ca²⁺ stores. This leads to reduced SR Ca²⁺ release, which induces additional Ca²⁺ influx during the plateau phase of the action potential, further slowing the decay of the Ca²⁺ transient. These changes can explain the defective Ca²⁺ transients of the failing human ventricular myocyte.